It remains poorly understood how serotonin circuits in the brain dysfunction in depression, drug addiction and other disorders. Understanding the role of serotonin neurotransmission in psychopathology is complicated by one of the most salient features of the serotonin system: its neuroanatomy. In this project we examine how serotonin neuron function changes in animal models of depression and nicotine abstinence, and after antidepressant treatment. Our work seeks to reconcile behavioral pharmacology with neuroanatomy to resolve some of the contradictory findings in the field. The over-riding hypothesis is that there are topographically organized changes in the activation of serotonin neurons in depression and these are resolved by antidepressant treatment. In addition, we examine how feedback inhibition mediated by 5-HT1A receptors changes in coordination with altered patterns of serotonin-neuron activity. Finally we examine the functional impact of topographically selective changes in activation state on behavior. The specific aims integrate cellular, systems and behavioral approaches to understand function and dysfunction of serotonin neurotransmission. The broad long-term goal of this research program is to provide a better understanding of the role of serotonin in affective and addictive disorders.